ABSTRACT Our overall goal is to devise a clinically translatable strategy to improve the function of aged lungs. Here we propose to develop a strategy to rejuvenate old lungs by altering the extracellular matrix (ECM) - the scaffold on which cells adhere and that can affect cell behavior, organ structure and mechanical properties. We have evidence that the lungs of aged mice have lower levels of several laminins. In addition, when human lung fibroblasts are cultured in decellularized lungs of aged mice, their expression of laminin alpha-4 (Lama4) is significantly reduced compared to when they are cultured in young lung matrix. They also alter their ECM gene expression profile when exposed to the aged lung ECM (compared to young ECM). Similarly, normal human lung epithelial cells express lower levels of laminin alpha-3 when cultured on aged decellularized lungs. Since ECM can direct cell behavior, a more encompassing way to make an impact on rejuvenation strategies is to alter the aged ?landscape?, i.e. reset the ECM to its younger state. We wish to test our central hypothesis that cell-mediated therapy can be used to replenish the foundational scaffold components that have declined with age, resulting in lungs with properties of younger lungs. In Aim 1, we will use intact, decellularized lung matrix (DLM) from aged mouse lungs as the natural foundational scaffolds that will be altered with Lama3 and/or Lama4-transfected stromal cells and anticipate that human lung fibroblasts will behave as they do in young DLM in vitro. In Aim 2, we will test the feasibility of altering the lung ECM and the mechanical properties of lungs of aged mice by using Lama3/4-transduced stromal cells in vivo as cell therapy. If successful, our work will provide insight into how aged versus young lung matrix affects lung fibroblast behavior and will provide preclinical evidence that cell-mediated therapy can be used to rejuvenate old lungs. The concept of an ECM ?reset? could open the avenue to a new approach to treat lung aging and lung diseases in general, as well as for other organ and vascular diseases associated with aging.